@article{8bf4718025a143588c7cdcdcf470f0e7,
title = "Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies",
abstract = "Second-generation antipsychotic exposure, in both children and adults, carries significant risk for excessive weight gain that varies widely across individuals. We queried common variation in key energy balance genes (FTO, MC4R, LEP, CNR1, FAAH) for their association with weight gain during the initial 8 weeks in the two NIMH Research Units on Pediatric Psychopharmacology Autism Network trials (N=225) of risperidone for treatment of irritability in children/adolescents aged 4-17 years with autism spectrum disorders. Variants in the cannabinoid receptor (CNR)-1 promoter (P=1.0×10-6), CNR1 (P=9.6×10-5) and the leptin (LEP) promoter (P=1.4×10 -4) conferred robust-independent risks for weight gain. A model combining these three variants was highly significant (P=1.3×10 -9) with a 0.85 effect size between lowest and highest risk groups. All results survived correction for multiple testing and were not dependent on dose, plasma level or ethnicity. We found no evidence for association with a reported functional variant in the endocannabinoid metabolic enzyme, fatty acid amide hydrolase, whereas body mass index-associated single-nucleotide polymorphisms in FTO and MC4R showed only trend associations. These data suggest a substantial genetic contribution of common variants in energy balance regulatory genes to individual antipsychoticassociated weight gain in children and adolescents, which supersedes findings from prior adult studies. The effects are robust enough to be detected after only 8 weeks and are more prominent in this largely treatment naive population. This study highlights compelling directions for further exploration of the pharmacogenetic basis of this concerning multifactorial adverse event.",
keywords = "Autistic disorder, CNR1, Children, Leptin, Risperidone, Weight gain",
author = "Nurmi, {E. L.} and Spilman, {S. L.} and F. Whelan and Scahill, {L. L.} and Aman, {M. G.} and McDougle, {C. J.} and Arnold, {L. E.} and B. Handen and C. Johnson and Sukhodolsky, {D. G.} and Posey, {D. J.} and L. Lecavalier and Stigler, {K. A.} and L. Ritz and E. Tierney and B. Vitiello and McCracken, {J. T.}",
note = "Funding Information: Acknowledgements. This work was partially supported by the following sources: NIMH grants T32MH073517 (ELN), K23 MH094613 (ELN), K24 MH010805 (JTM) and N01MH70010 (JTM), N01MH80011 and U10MH66768 (MGA), N01MH70001 and U10MH66766 (CJM), N01MH70009 and U10MH66764 (LLS) and a grant from the Korczak Foundation (LLS). Study medications were donated by Janssen Pharmaceutica. Funding Information: Dr Aman has received consulting fees from Bristol-Myers Squibb, BioMarin, Roche and Supernus. Dr Aman also reports research support from Bristol-Myers Squibb and Johnson and Johnson. Dr Arnold has received research funding from Curemark, Shire and Lilly, and has consulted on advisory boards for AstraZeneca, Biomarin, Novartis, Noven, Seaside Therapeutics and Shire. Dr Handen reports research support from Eli Lilly, Curemark and Bristol Myers Squibb. Dr McCracken reports receiving consulting fees from BioMarin, Novartis and PharmaNet; he also reports research support from Bristol-Myers Squibb, Roche and Seaside Therapeutics. Dr McDougle reports having received consultant fees from Bristol-Myers Squibb, Hoffman-LaRoche and Forest Research Institute; he has also received research support and is on the speakers{\textquoteright} bureau of Bristol-Myers Squibb. Dr Scahill reports receiving consultant fees from Brackett, Pfizer, Hoffman, BioMarin; he has also received research support from Pfizer, Shire and Hoffman. Dr Stigler reports receiving research support from Bristol-Myers Squibb, Eli Lilly, Jansen, Novartis, Forest Research Institute and Seaside Therapeutics. The remaining authors declare no conflict of interest.",
year = "2013",
doi = "10.1038/tp.2013.26",
language = "English (US)",
volume = "3",
journal = "Translational psychiatry",
issn = "2158-3188",
publisher = "Nature Publishing Group",
}